The UCI team conducted tests to see how neuropeptide S (NPS) affected behavioral responses in rodents. They found that NPS increases alertness, suppresses sleep and even controls stress responses. This establishes NPS, which was first discovered in 2002, as an important modulator of sleep and alertness. This study also suggests NPS has potential as a target for new drugs to treat sleep disorders. The study appears in the Aug. 19 issue of Neuron.
"Since our knowledge of NPS is so new, we may be at the tip of the iceberg in understanding its function," said Rainer Reinscheid, assistant adjunct professor in pharmacology and lead researcher in the study. "We've found NPS to be so active with sleep and anxiety behavior that it can be a very attractive drug target, both to enhance and to suppress its function."
In testing how NPS is involved with both sleep regulation and stress behaviors, the researchers found that NPS is produced by previously unidentified neurons in a brain stem region known for regulating arousal and anxiety. Further tests demonstrated that rats injected with NPS showed increased alertness and reduced slow-wave and REM sleep over untreated rats.
NPS receptor proteins were also detected in stress-related brain regions such as the amygdala and thalamus. In behavior tests that measure their stress-related anxiety, mice injected with NPS show fewer anxiety responses and increased activity than untreated mice. Sleep and fatigue are in a balance - insufficient sleep will increase fatigue, and only sleeping can reduce fatigue. There is a variety of sleep and fatigue disorders, which range from the most severe affecting only a set of individuals to mild ones nearly everyone will encounter.
The most severe form of sleep disorder is narcolepsy, in which affected individuals suffer from irresistible sleep attacks. Most common is the excessive daytime sleepiness that may result from chronic sleep deprivation or sleep impairments. Very little is known about the basic mechanisms that regulate these physiological responses, but the UCI study provides a first glance at a neuropeptide that affects these sleep mechanisms.
"Some 100,000 Americans are currently treated for excessive daytime sleepiness, but the number of the undiagnosed is far larger," said study co-author Olivier Civelli, the Eric L. and Lila D. Nelson Chair in Neuropharmacology at UCI. "Furthermore, symptoms of sleepiness, often recognized as fatigue, are associated with numerous other illnesses, such as multiple sclerosis, Parkinson's disease and also depression. If it can be shown that the NPS system is a major modulator of fatigue, then its therapeutic potentials will be immense."
Yan-Ling Xu of UCI is a co-lead author on the study. Other participants are Stewart D. Clark, Zhiwei Wang, Steven H. Lin, Fernando A. Brucher, Joanne Zeng and Nga K. Ly of UCI; and Salvador Huitron-Resendiz, Steven J. Henriksen and Luis de Lecea of the Scripps Research Institute in La Jolla, Calif. The National Institutes of Health and the Stanley Medical Research Institute supported the research. UCI has applied for a patent for the pharmaceutical use of the NPS protein.
NPS exerts its action by binding with a particular G protein-coupled receptor. GPRCs, as they are called, are a group of proteins that are the most important regulators of the central nervous system. Research on GPRCs has offered new insights into the understanding of particular brain functions and the receptors are popular targets for new drugs to treat a host of brain disorders.
Experiments by the UCI team revealed that NPS is expressed discretely in a few brain areas. But its strongest expression is in a previously unidentified cluster of neurons located next to locus coeruleus (LC) neurons, a brain stem region known for regulating arousal and anxiety. LC neurons fire signals into the cerebral cortex to promote arousal and are inactive during periods of sleep. By identifying this new cluster of neurons, the UCI researchers have also begun to dissect the diverse functions attributed to the LC at an anatomical level, a discovery that will have major repercussions on the understanding of this brain area.
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